Transforming Growth Factor (TGF)-β is a cytokine involved in various physiological phenomena such as acceleration or suppression of cell growth, cell differentiation, development and the like. Pathologically, moreover, it is known to cause diseases closely related to the fibrillization of organ, such as cancer, cirrhosis, renal failure (glomerulonephritis), arteriosclerosis, rheumatoid arthritis and the like (non-patent document 1).
TGF-β forms TGF-β superfamily together with bone morphogenetic factors, activin and the like, since they show homology in the constituent amino acid. The members of the TGF-β superfamily are all synthesized as precursors, after which pre-form and then pro-form sequences are eliminated by protease, whereby a mature protein with a molecular weight of about 12 kDa is formed. Since two such monomers form a covalent bond by disulfide bridging, a dimer with a molecular weight of about 25 kDa is formed (non-patent document 2).
Human TGF-β includes three kinds of isoforms (TGF-β1, TGF-β2 and TGF-β3), which are expressed in a tissue specific manner (non-patent document 2). The signal of each TGF-β isoform is transmitted via a signal transduction pathway, and exerts each physiological action. That is, when TGF-β is bound to a type II TGF-β receptor, which is a receptor-like serine/threonine kinase, a receptor complex consisting of two molecules of type II receptor and two molecules of type I TGF-βreceptor/Alk-5 is formed, and type II receptor phosphorylates a serine residue of type I TGF-β receptor/Alk-5 and activates it. Type I TGF-β receptor/Alk-5 is also a serine/threonine kinase, like type II receptor, and activated type I receptor/Alk-5 phosphorylates a serine residue of Smad2 or Smad3, which is a transcription factor present in the cytoplasm. The phosphorylated Smad2 or Smad3 forms a complex with Smad4 in the cytoplasm, are thereafter transferred to the nucleus, bound to a target sequence called CAGA box present in a promoter region of a collagen gene which is a target gene deeply involved in the fibrillization, and induce transcription expression together with a co-activator (non-patent documents 1, 3, 4).
As a means to improve pathology caused by the action of TGF-β, attempts have been made to inhibit binding of TGF-β and a receptor by a neutralization antibody, a soluble receptor or a low-molecular-weight compound, inhibit the kinase activity of a receptor, which is caused by binding of TGF-β, with a low-molecular-weight compound and the like. However, the development of a novel TGF-β signal transduction inhibitor has been desired (non-patent document 5).
On the other hand, non-patent document 6 discloses N-substituted piperidinyl-diphenylsulfonyl-sulfoneamides that inhibit secreted Frezzled-Related Protein I (sFRP-1) and control Wnt signaling (non-patent document 6).